Process for the production of 11beta, 12beta-epoxypregnane-3, 20-dione



Oct. 20, 1964 Filed March 2l, 1957 BROMINATION AGYLATION oxmATloN mlUODOl--OZ AGYL- 0 OH Rl OXIDATION HYROLYSIS HEMISUOGlNYL-O P. L. JULIAN ETAL PROCESS FOR THE PRODUCTION OF ll,l2-EPOXYPREGNANEI-3,EO-DIONE 2 Sheets-Sheet 1 o :5 In" E 0;06 |22 l 4 :III D Q-O O-O Z o l n n n a? NVENTORS PERCY L. JULIAN as BY ARTHUR MAGNANI @M2/MQW ATTORNEYS Oct. 20, 1964 P. JULIAN ETAL 3,153,646

PROCESS FOR TRE: PRODUCTION OF 115,12-EPOxYRREGNANE-s,zO-DIONE Filed March 21, 1957 2 Sheets-Sheet 2 R9 AN ALIPHATlc HvoRocARaoN GROUP INVNTgSa HAVING To 5 CARBON nous PERCY L J L| ARTHUR MAGNAN| RIO AN AUPHATIO HYnnocAReoN eRouP BY HAvuNs l To 5 cARaoN nous on AN ALIPNnlc 0u cANaoxY HvuRocARaoN MMYM HAvlNo 2 To s cARaoN nous A aoNn 1N TNEGoR PosmoN ATTORNEYS United States Patent s 153 646 Puocrzss non THE PRDUcTroN oF 11ans- EPoxYPnEGNANa-sno-DIONE Percy L. Julian, Oak Park, and Arthur Magnani,

Wilmette, lll., assignors, by mesne assignments, to Smith e & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania Filed Mar. 21, 1957, Ser. No. 647,465

3 Claims. (Cl. 26d-239.55)

in which: R5 and R7 individually represent hydrogen and, when taken together, represent a carbon to carbon bond;

R8 is -l-l, OI-I, an aliphatic acyloxy group having from 2 to 6 carbon atoms, an aliphatic w carboxyacyloxy group having from 3 to 6 carbon atoms, preferably hemisuccinyloxy, or an alkali metal salt of an w carboxyacyloxy group having from 3 to 6 carbon atoms;

The designation 5, as used herein, represents a bond in the a or position.

It will be understood that the above structural formula, as used herein and in the claims, covers allopregnanes as Well as pregnanes and A4 pregnenes.

The principal pharmacological activity of these compounds is as central nervous system depressants. They are useful, for example, as sedatives, anesthetics and analgetics. They also have utility as valuable intermediates. In addition to having these activities in humans, they are useful as general anesthetics for laboratory animals such as mice or rats.

Advantageous compounds as far as depressant activity is concerned are the ring A saturated 11,12epoxy compounds in the pregnane series, for instance compounds of the following structural formula:

in which:

R8 is hydroxyl, hydrogen, an aliphatic acyloxy group having from 2 to 4 carbon atoms, an aliphatic w carboxy- ICC acyloxy group having lfrom 3 to 4 carbon atoms, preferably hemisuccinyloxy, or an alkali metal salt of an w carboxyacyloxy group having from 3 to 4 carbon atoms.

Preferred compounds are where RB is hydrogen or sodium succinyl. 1l,l2epoxypregnane3,20-dione-21-olsodium succinatel is particularly useful for application where a soluble depressant is desirable, for instance intravenous anesthesiology.

The compounds of this invention also have utility as intermediates in the preparation of known physiologically active steroids. For example, the 1l,12epoxypreg nahe-3,20-dione and ll,l2-epoxyallopregnane-3,Z0-dione members of this series have utility as intermediates in the synthesis of the pregnane and allopregnane 3,1l,20- triones which are recognized as valuable for the synthesis of the corticoid steroids. For instance, the 11,12-epoxy ring is opened with a hydrohalic acid, such as by hydrobromic acid. The ll-hydroxyl group is oxidized for instance with chromic acid in aqueous acetic acid. The resulting l2-bromotrione is debrominated with zinc and acetic acid to form the desired pregnane-3,ll,20trione and allopregnane-3,l1,20-trione.

The ZI-hydroxylated members of the series are also useful in preparing biologically active compounds, such as corticosterone acetate. A typical route is starting from 11,8,12-epoxypregnane3,ZO-dione-Zl-ol acetate, a compound of this invention, by opening the 1l,12 epoxy ring with hydrogen bromide to give the 12-bromo- 11-ol which is oxidized with chromic oxide in pyridine and debrominated with zinc-acetic acid to give pregnanc- 3,l1,20trione2lol 21acetate. The A4 double bond may then be inserted by bromination at 4 followed by dehydrohalogenation with pyridine, all following the method of Reichstein, Helv. Chim. Acta, 26, 747 (1943), to give the desired corticosterone acetate.

The 1l,12epoxypropgesterone of this invention is converted to valuable steroids having progestational activity, for instance 9-dehydroprogesterine, by opening the epoxy ring with hydrogen halide, removing the halide atom withRaney nickel and dehydrating with thionyl chloride to introduce the M911) moiety [Shoppee and Reichstein, Helv. Chim. Acta, 24, 351 (1941)]..

Other objects of this invention will become apparent on reading the following description in conjunction with the drawings in which:

FIGURE 1 is a schematic representation of the process for obtaining Ithe starting materials required for the process of this invention;

FlGURE 2 is a schematic representation of the process in accordance With this invention.

With respect to the following description, it is desired to point out that reduction providing an OH group in the 12-position results in a mixture of compounds, some having the OH bonded by a bond in the a position and some by a bond in the position.

It is also desired to point out that the ring A saturated steroid compounds disclosed as intermediates in preparing the compounds of this invention exist in either the 3a,5 or 3,5a form. The structural formulas in the description and claims are intended to cover both of these forms of ring A saturated steroids.

Where the term aliphatic is employed herein, the preferred form is an alkane.

PREPARATION 0F l1 ,8,12 EPOXIDE STARTING MATERIALS The starting materials for the process of this invention, namely, the ll,12epoxides of Formula Xl (FIGURE 2) are prepared as fully disclosed in our copending apo plication, Serial No. 643,353, iiled March 1, 1957, now Pat. No. 2,940,991. Their preparation is shown schematically in FIGURE 1 to which reference will now be made.

The starting materials are either well known or obvious to those skilled in the art. The desired pregnane-3a,12a, e-triol starting material is produced from the known pregnane-Ba,l2a-diol-20-one diacetate which can be 0btained from desoxycholic acid, by reduction of the ZO-keto group using either a chemical reducing agent, such as a bimetallic anhydride, for instance sodium borohydride in an aqueous organic solvent, such as aqueous methanol or lithium aluminum hydride in a dry organic solvent, such as ethyl ether or tetrahydrofuran, or catalytically, for instance With hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel in alcoholic solution. The resulting diacetate is hydrolyzed to the 3a,12x,2G,6-triol with an alkaline solution, for instance with potassium hydroxide or sodium hydroxide in aqueous methanol.

The known allopregnane-3-ol-l2,20-dione acetate, obtained from hecogenin by typical genin degradative oxidation of the pseudoacetate with chromium oxide, is similarly reduced to give the allopregnane-B,12,8,20-triol starting material. v

As illustrated in FIGURE 1, the pregnane or allopregnanc-triol (I) selected, depending upon the end product trione desired, is preferentially ozidized at position 112. Blocking the hydroxyl groups in the 3 and 20 position is essential in order to accomplish a clean-cut reaction. This is accomplished by blocking these positions with a suitable acyl group, for example, either an aromatic acyl group such as benzoyl, hemiphthalate or toluyl or by a lower -alkanoyl group such as propionyl, butyryl or preferably by an acetyl or hemisuccinyl group. Acylation is accomplished by acylating with the appropriate acyl anhydride or acyl chloride in basic solution such as in an excess of a tertiary amine, for instance pyridine, collidine or picoline or in an inert solvent such as dimethylformamide, acetone or dmethylacetamide With about one equivalent of an acid binding agent, for instance pyridine, tributylamine or picoline. The resulting 3,12,20-triol 3,20-diacylate (II) then is oxidized With a suitable oxidizing agent, for example, chromic acid in aqueous acid solution, for example, aqueous acetic acid or chromic oxide in basic solution, for example, in pyridine solution, to form the corresponding 3,20-diol-l2-one diacylate (III).

When the 3,20Lblocking acyl groups contain centers reactive under the bromination conditions later employed in the process, it is necessary to hydrolyze the blocking groups after the oxidation step and reacylate to introduce nonreactive blocking groups, preferably acetate. As an example of a blocking group reactive to bromine, the hemidibasic esters are mentioned, for instance the hemisuccinyl and the herniphthalate moieties. By Way of specie example, the procedure where the hemisuccinyl moiety is employed is as follows: Diacylation With, for example, succinyl anhydride in an excess of tertiary amine, such as pyridine, or in an inert solvent, such as dimethylformamide, acetone or dioxane with an equivalent of acid binding agent, for example, pyridine, tributylamine or picoline, normally first produces a mixture of the monoand dihemisuccinates. The monohemisuccinate upon retreatment, produces a further quantity of the dihemisuccinate (IV). The thus formed 3,20-dihemisuccinate (IV) then is oxidized with an oxidizing agent, as described above, preferably with chromic acid in aqueous acetic acid solution or with chromic oxide in pyridine solution to the desired 3,2(),3-dio1-12-one dihemisuccinate. The protective groups in the 3 and 20-positions then are hydrolyzed by alkali, for example, potassium or sodium hydroxide in alcohol, for example, methanol or isopropanol or in an aqueous alcohol mixture, for example, aqueous methanol, ethanol, isopropanol or butanol. The resulting 3,20-dioll2-one (V) can then be diacylated With nonreactive acyl 'groups inert to bromine (using the same procedure as described above in connection with the 3,20 acylation of 3,12,20-triol (I) to the diacylate II) to produce the corresponding 3,20diol-12one diacylate (III) in which there are no acyl groups reactive during the bromination step. The better yields obtained by using this alternative procedure are due to the favorable solubility characteristics of the hemisuccinate derivatives.

The diacylate (III) containing the inert to bromine 3,20 blocking agents is brominated in an inert organic solvent, for example, chloroform, chloroform-acetic acid or ethylene dichloride by treatment With bromine at moderate temperature, from about 15 C. to about 40 C., preferably at about 25 C. The bromination can be catalyzed by and hence is preferably carried out in the presence of I-IBr. A mixture of 11a (VI) and llbromo isomers results. The 11a isomer is required for the formation of the 11,12-epoxide; preferably, therefore, the organic extract from the bromination reaction may be concentrated and the isomers separated by fractional crystallization from, for example, methanol or ethanol. The resulting 11a bromo-3,20diol12one diacylate (VI) then is reduced with a bimetallic hydride in an organic solvent such as sodium borohydride in an aqueous organic solvent inert to reduction, such as aqueous methanol or ethanol, or lithiumaluminum hydride in a dry organic solvent, such as diethyl ether, dibutyl ether or tetrahydrofuran at moderate temperatures, preferably from about 15 C. to about 40 C. to form a mixture of the lla-bromo-3,l2,20-trio1 (VII) and its 3,20 acylate. If desired, the mixture of the acylated and free triol can be reacylated using the appropriate acyl anhydride or acyl chloride, for example, those set forth above in connection with the formation of the diacylate Compound III in a tertiary base such as pyridine or in an inert solvent such as dimethylformamide, acetone or dioxane employing about one equivalent of an acid binding agent, for example, pyridine, tributylamine or picoline. If desired, the acyl groups can be removed by hydrolysis before the reduction step.

The triol (VII) its 3,20 acylate or a mixture thereof then is converted to the 1l-12-epoxy-3,20 diol (VIII) with a strong dehydrohalogenating agent such as a strong base such as caustic alkali, for example, potassium hydroxide or sodium hydroxide in aqueous methanol, isopropanol or ethanol or such as collidine or such as silver oxide-pyridine. This compound is the desired starting material XI (FIGURE 2) for the process claimed herein.

PREPARATION OF COMPOUNDS OF THIS INVENTION The compounds of this invention are prepared by several routes, all of which have the same initial step, namely, oxidation of the 1l,12-epoxy-3,20,@-diol (Compound XI), for instance With chromic acid in acid solution for instance such as in acetic acid or chromic oxide in basic solution for instance in an excess of pyridine. The product of this oxidation step is the 11,8,12-epoxy-3,20dione (XII), which has great value both as an intermediate in the preparation of the other compounds of this invention and as a pharmacologically active agent, particularly as a sedative and anesthetic.

The A4 analogues of this series are advantageously prepared by opening the 11,12-epoxy ring of XII with a hydrohalic acid, for instance hydrobromic or hydrochloric acid, in aqueous-organic solution, such as aqueous ethanol or acetone, or with hydrogen chloride or bromide in an anhydrous organic solvent, for instance benzene or dioxane. The resulting 11,12-halohydrin (XIII) is brominated at the 4 position (using, for example, bromine in an inert organic solvent such as methylene chloride or dimethylformamide) to form Compound XIV and dehydrohalogenated at the 4,5 position with a dehydrohalogenating agent, such as lithium chloride in dimethylformamide to form the 12a-bromo-A4-pre'gnene-l l-ol- 3,20-dione (XV). Other known methods of introducing' the 3-keto-A4 system can be used, for example, dehydro halogenation of 3-keto-4-bromo v'compound with tertiary amines such as pyridine or collidine. This compound is then reacted with alkali such as potassium carbonate, in aqueous methanol to form the desired 11,12epoxy-A4 pregnene-3,20dione (XVI).

The 21-acylates, which also are members of this series, are prepared by reducing the 3-keto group of 115,121?- epoxypregnane-3,20dione (XII), for instance with a bi-` metallic hydride, such as sodium borohydride in aqueous methanol under basic conditions. The resulting compound, 1l,12epoxy3ol20one has unexpected central nervous system depressant activity and will be claimed in a copending application. The 11,12 epoxy-3-ol (XVII) is reacted with a hydrohalic acid, for example, hydrobromic acid, in aqueous-organic solution, such as aqueous ethanol or acetone, or with hydrogen chloride or bromide in an anhydrous organic solvent, for instance benzene or dioxane to open the epoxy ring and form the 12-halo-3,1l-diol-ZO-one (XVIII) which, in turn, is brominated at the 21-position using, for example, bromine in an inert organic solvent such as glacial acetic acid, methylene chloride or dimethylformamide preferably in the presence of a catalytic amount of hydrogen bromide. The resulting 12,21-dibromo3,1l-diol-20-one (XIX) is then reacted with a suitable alkali salt of the desired acylate, for instance sodium acetate, sodium propionate, potassium valerate or sodium caproate, in a non-reactive aqueous miscible solvent, such as acetone or methyl ethyl ketone to insert a 2l-acyloxy group. Preferably, a mild base such as sodium carbonate or potassium bicarbonate is added to the reaction mixture to assist in forming the 11,12-epoxy ring in the same reaction mixture. Alternatively, this reaction may be run independently.

The resulting compounds (XX) are oxidized preferably with chromic acid or chromic oxide in acid solution or basic solution as herein above described to form the desired members of this invention, the 11,l2,B-epoxy-2l ol-3,20dione acylates (XXI).

These compounds, for instance the 11,6,12-epoxy-21- of-3,20dione 21-acetate (XXI), are hydrolyzed at the 2l-position under mild conditions (employing, for example, a sodium methoxide-methanol solution) -to give the 1l,l2-epoxy-21-ol-3,20dione (XXII) a particularly useful intermediate which may be further acylated to obtain other esters (XXXIII) of this invention, such as the hemisuccinate, methyl succinate, acetate, benzoate'or isovalerate. This is the preferred Way to form esters of dibasic acids and higher monobasic fatty acids.

Where esters are formed from dibasic acids, hemiesters result. It Will be understood that alkali metal salts can then be formed by reaction with the unreacted carboxyl group, for example, sodium or potassium salts.

The epoxy compounds of this invention containing both the 2l-acyloxy group and the A4 unsaturation are advantageously prepared from the 1l,l2epoxy-2lol3,20 dione esters (XXI), such las the 21-acetate. The epoxy ring is opened as described above, for instance With an aqueous alcohol solution` of hydrobromic acid. The resulting 11,12-halohydrin (XXIV) is then brominated at position 4 (using, for example, bromine in an inert organic solvent such as methylene chloride or dimethylformamide) to form the Compound XXV and then dehydrohalogenated'either with dimethyl formamide as previously described or with an organic base such as pyridine. The product, l2a.bromo-A4pregnene11,8,21- diol-3,20- dione ester (XXVI), is then dehydrohalogenated with a mild alkaline agent such as sodium bicarbonate or potassium bicarbonate in acetone at reflux to give the the desired epoxy-A4 esters (XXVII). These esters can be hydrolyzed under mild conditions (employing, for example, a sodium methoxide-methanol solution) to substitute 6 a hydroxy group in the 21-position in place of the acyloxy group. Y

The a,aepoxy analogues are prepared by reacting the corresponding Alllz compounds with a peracid, such as peracetic acid or preferably monoperphthalic acid in an organic solvent inert to the oxidizing agent, such as ethyl ether.

These, ecm-epoxy analogues also have utility as intermediates in addition to their sedative activity. The ,aepoxy rings of the 3,20-diones of this invention can be advantageously opened with hydrohalic acids to give llhalo-12-hydroxy derivatives. These compounds can be further treated to introduce the 3-keto-A415 system, thereby producing a series of biologically active progesterone analogues, for example, having glucocorticoid and desoxycorticosterone-like activity.

For instance, l1,12aepoxypregnane 3,20 dione is reacted vvith alcoholic hydrobromic acid to open the epoxide ring and form the ll-bromo-l2-hydroxy compound which can be selectively brominated at 4 with one equivalent of bromine and dehydrohalogenated usingV dimethyl formamide -to give 11a-bromo-12-hydroxyprogesterone, a compound with appreciable glucocorticoid activity.

EXAMPLE I Oxidation of 11[3,12Epoxypregnane-3,20Diol (a) ACID SOLUTION A mixture of 50 g. of 11,5,12-epoxypregnane-3,2013- diol, 50 cc. of pyridine, 400 cc. of acetic acid and 20 cc. of Water is cooled to about 15 C. A solution consisting of 40 g. of chromic acid, 50 cc. of Water and 100 cc. of acetic acid is added rapidly and the mixture cooled to about 15 C. The resulting mass is permitted to warm up to 25 C., at which temperature it is agitated for four hours. The mass is diluted with 4 l. of Water and extracted with methylene chloride. The solvent solution is Washed with Water, 10% aqueous caustic soda and finally with Water until the washings are neutral to litmus. The washed extract is evaporated to dryness. The residue is dissolved in methanol. ,The resultant solution, concentrated to a volume of 60 cc., is set aside to crystallize slowly; 24.1 g. of 11,8,12-epoxypregnane-3,20-dione, M.P. 139-142 C. Recrystiallization from methanol gives crystals Which melt at 143-5 C.

(l1) BASIC SOLUTION A solution of 2 g. of 1l,12epoxypregnane-3a,20 diol in 20 cc. of pyridine is added to a suspension of 3 g. of chromic oxide in 30 cc. of pyridine [prepared as described in I. Am. Chem. Soc., 75, 427 (1953)]. The mixture is agitated for 45 minutes and then permitted to stand for about 16 hours. The dark solution containing a dark precipitate is diluted with 400 cc. of Water and filtered. The clarified ltrate is extracted With methylene zza-BromopregnaneuJ-oZ-azo-Dfone To a solution of 34.3 g. of the epoxydione of Example I in 450 cc. of acetone, cc. of 4 N hydrobromic acid is added. The mixture is agitated and cooled as the bromohydrin rapidly precipitates with the evolution of heat. The slurry is ltered and washed with 50% acetone. After drying, 40.5 g. of l2tx-bromopregnane-1l-ol- 3,20-dione, M.P. Z39-240 C. are obtained.

In an analogous fashion, by treatment of an acetone solution of the epoxydione with aqueous hydrochloric acid, the chlorohydrin is obtained. By use of aqueous hydrouoric acid, the iluorohydrin is prepared.

EXAMPLE lll 4,1 Z-Dbromopregnane-l 1 ,B-0l-3,20Dz'one A portion of a solution of 11 g. of bromine dissolved in 100 cc. of dimethylformamide is added to a suspension of 25.6 g. of the bromohydrin prepared in Example 1I above, in 250 cc. of dirnethylforrnamide with 400 mg. of p-toluene sulfonic acid. The mixture is agitated and heated to 45 C. to initiate the reaction. After 15 minutes, the mass becomes decolorized and the balance of the bromine solution is added to the warm (3S-4G C.) mixture over a period of two hours. The mass is agitated for minutes and then diluted with 400 cc. of water (slowly and while cooling). The resulant slurry is vfiltered. The filter cake is washed with water. After drying, 28 g. of 4,12-dibromopregnane-11-ol-3,20-dione,. MP. 205 C. (dec.) is obtained. Upon recrystallizatiorr from acetone, the product melts at 21S-220 C..

EXAMPLE 1V 12zc-Brom@A4-Pregnana] 1 ,6-OZ-20-Dz'one A mixture of 21.8 g. of the dibromo compound of' Example III, 175 cc. of dimethylformamide, and 5.7' gf..

of lithium chloride is heated in an atmosphere of nitrogen at 94-96 C. for three hours. The pale yellow solution, diluted with 125 cc. of water, forms 'a slurry which.

is cooled and filtered. In this manner, 14.5 g. of l2cais obtained.

EXAMPLE V A mixture of 2.97 g. of the bromohydrin of Example IV, 3) cc. of methanol, 6 cc. of water and 1.5 g. of p0- tassium carbonate crystals is heated under reiiux for 15 minutes. The mass is concentrated to the boiling point and diluted with water. The mixture is extracted with methylene chloride. The extract is washed with water and evaporated to dryness. The residue, crystallized from acetone, yields 11,8,12-epoxy-A4-pregnene-3,2Q- dione, M. 16S-170 C.

EXAMPLE VI A mixture of 5.0 g. of 1lf3,12-epoxyallopregnane-3ot- ZO-diol, 5 cc. of pyridine, 40 cc. Vof acetic acid and 5 cc. of water is cooled externally while a solution of 4 g. of chrornic acid is aqueous acetic acid is added. The reaction mixture is lallowed'to stand at room temperature for tive hours with agitation. After dilution with Water, the mixture is extracted cxhaustively with methylene chloride. The organic extracts are washed with alkali solution and water. The dried methylene chloride extract is concentrated to dryness in vacuo. The residue is recrys'- tallized from methanol to yield the pure solid', 1l [3,123- epoxya11opregnane-3,2Q-dione.

' EXAMPLE VIH ]2-Brom0pregnaize-3a,l I-Dol-Zd-One A solution of 5 g. or llfl1-epoxypregnane3,20 dione, made as -in- Example l, in 8O cc. ofmethanol cooled to 25 C. is treated with a solution consisting of 200 Ling. of sodium borohydride, l0 cc. of pyridine, 10 cc. of methanol and 1.5 cc. of 10% aqueous sodium hydroxide. The mixture warms spontaneously to 34 C. .and a clear solution results. The mass is agitated for 15 rninutes and 500 cc. of water added slowly. The resultant slurry is permitted to stand for one hour, then ltered. The lter cake is washed with water and dried. The resultant product, NLP. 13G-140 C. (combined with :a small amount of product obtained by extraction with lether of the mother liquor) is dissolved in methanol. "The resulting solution, after iltration, is concentrated to .about l5 cc. volume. Five cubic centimeters of 4 N hydrobromic acid are added and the resultant solution set taside to crystallize. The slurry is filtered. The filter fcalre is washed with aqeous methanol. The crude 12- bromopregnane-3oc,1l-diol-ZO-one melts at M50-183 C. Recrystallization from methanol gives bromohydrin melting at 187-189" C. (dec).

EXAMPLE iX 12,21 -Dibromopregnane-S 0:,1 1,6-D0Z-20-0ne A solution of 5 g. of brornine in 60 cc. of methylene chloride is added dropwise over 2O minutes to a solution of `12.5 g. of the bromohydrin from Example VIH in 400 cc. of methylene chioride and l cc. of methanol. The mass is agitated for 5 minutes, and then washed with water, aqueous sodium bicarbonate and, iinally, with water. The washed solution is concentrated to incipient crystallization and cooled to below 5 C. In this fashion, 12,2l-dibromopregnane-Bll-diol-ZO-one, MP. 182 C. (dec.) is obtained.

EXAMPLE X 1 l ,8,1 2-Epoxypregnane-3 0:,21 -DoI-ZO-One 2] -A cetate h A'mixture consisting of 1.5 g. of the 12,2l-dibromo derivatlve, prepared as in Example IX above, `25 cc. of acetone, 3.75 g. of potassium acetate and 330 mg. of sodium bicarbonate is heated under reiux for five hours. The acetone is removed by distillation and the residue diluted with water. The resultantr mass is extracted with ether. The ether extract is washed with Water. The ether solution, dried over anhydrous sodium sulfate, is evaporated'to a low volume. By the addition of petroleum ether, crystallization of the product, 11,12epoxy pregnane-Sa-Zl-diol-ZO-one 2l-acetate, 157-159 C. is induced.

EXAMPLE XI lI,1Z-Epoxypregnane-Zl-Ol-3,20-D0ne A cetate A solution of 1.27 g. of the epoxy-Zl-acetate, prepared as in Example X above, in 5 cc..of pyridine is added to a mixture of 1.5 g. of chromium trioxide and l5 cc. of pyridine, using about 2 cc. of pyridine to assist in the transfer. The mitxure is agitated at ambient temperature for about 20 hours, and then ether and water is added. The ether layer is washed with water and liltered. The solution is washed with water, dilute sodium hydroxide and, iinally, with Water. The washed solution is evaporated to dryness, taking off the last traces of solvent in vacuo. The residue is crystallized from ether to give ll,IZ-epOXypregnane-Z1ol3,20dione acetate, MP. 117-119 C.

The 11,12-epoxy-21-acetate is converted, by reaction with halogen acids such as hydrobromic acid to the 11(3- hydroxy-lZ-halo derivative which, upon oxidation with chromic acid followed by dehalogenation with zinc and acetic acid, results in p1egnane2lol-3,11,20-trione acetate. Introduction of the 4,5 double bond in aknown manner converts this compound into corticosterone acetate.

9 EXAMPLE XII Several drops of sodium methoxide-methanol solution are added to a solution of 500 mg. of the epoxydione acetate from Example XI in l cc. of methanol. After standing at room temperature overnight, the solution is neutralized with a drop of dilute acetic acid and concentrated in vacuo. The residue is recrystallized from ether to give crystals of 11,12epoxypregnane-2l-ol-3,20di

one.

EXAMPLE XIII Following the procedure of Example X, 2.0 g. of the 12,2l-dibromo compound is reacted With 4.2 g. of sodium propionate and 400 mg. of sodium bicarbonate to give 1 1(3,12/3-epoxypregnane-3 @-2 1-diol-20-one 2 l-propionate which, in turn, is oxidized with 1.7 g. of chromium trioxide in cc. of pyridine to give the 21-propionate of 11,l2epoxypregnane2l-ol-3,20dione.

A solution of 1.0 g. of the 2l-ol (prepared as in Example XII) in cc. of acetone with 0.5 g. of dry pyridine is mixed with 0.5 g. of succinic anhydride. After standing overnight at room temperature, the reaction mixture is quenched in ice water and filtered. The resulting solid is recrystallized from methanol-petroleum ether to give crystals of the hemisuccinate ester.

A solution of 500 mg. of the hemisuccinate is dissolved in 100 cc. of dry ethyl ether. A small piece of sodium is added. With warming and swirling, a solid forms which is separated by filtration and washed With ether to separate the sodium salt.

EXAMPLE XV A solution of 5.0 g. of l1,8,l2-epoxypregnane-2l-ol- 3,20-dione acetate, prepared as in Example XI, in 25 cc. of purified dioxane is mixed with l() cc. of hydrogen bromide-dioxane solution. After standing at room temperature for several hours, the solution is evaporated in vacuo to leave a crude residue which, after recrystallization from methanol, gives l2-bromopregnane-ll,2l-diol 3,20-dione 2l-acetate.

To a solution of 5.3 g. of the 12-bromo compound in 50 cc. of dimethylformamide with a trace of p-toluene sulfonic acid, a solution of 2.2 g. of bromine in 25 cc. of dimethylformamide is added dropwise With agitation. The mixture is agitated with slight warming until the bromine color has largely disappeared. Quenching in water gives crude 4,12-dibromopregnane-1l,2ldiol3,20 dione 2l-acetate. A solution of 5.0 g. of this dibromo compound in 50 cc. of pyridine is heated to dehydrobrominate at 4,5 in the standard manner. The resulting compound, 1.5 g. is heated in a suspension of 25 cc. of acetone, 3.7 g. of potassium acetate and 330 mg. of sodium bicarbonate at reflux with stirring for several hours. After taking of the acetone in vacuo, the residue is diluted with water and extracted into ether. The dried ether extracts are evaporated and diluted with petroleum ether to separate l1,8,1Z-epoxy-A4pregnene3,20dione- 21-ol acetate.

A solution of 750 mg. of the acetate in 25 cc. of acetone-water is made slightly basic with several drops of` sodium hydroxide solution. After stirring at room temperature shortly, the reaction mixture is neutralized with dilute acetic acid and evaporated to give crystals of l 1,12epox A4pregnene3 ,20-dione-2 l-ol.

What is claimed is:

1. The method of making chemical compounds selected from the group consisting of 11,8,l2-epoxypregnane- 3,20-dione and 111S,12-epoxyallopregnane-3,ZO-dione 10 f which comprises oxidizing a compound having the following formula: l

EOMN

in which the designation represents a bond in a position selected from the and positions using an oxidizing agent selected from the group consisting of chromic acid in acetic acid and chromic oxide in pyridine.

2. The method of forming a chemical compound having thte following formula:

te CHOH to form the corresponding 3,20-dione, reducing the 3- keto group with sodium borohydride in aqueous methanol to form the corresponding 3ol,20one, reacting the 3-01 with a hydrohalic acid in a solvent selected from the group consisting of aqueous ethanol, aqueous acetone, benzene and dioxane to open the epoxy ring and form the corresponding l2tat-halo-11aol,v brominating using bromine in an organic solvent selected from the group consisting of glacial acetic acid, methylenechloride and dimethylformamide the thus formed compound at the 21-position, reacting in acetone the thus formed 12,21- dibnomo compound with an alkali metal salt of the desired acylate to insert a 2l-acyloxy group and reform the 1118,12-epoxy ring, and oxidizing using an oxidizing agent selected from the group consisting of chromic acid in acetic acid and chronn'c oxide in pyridine the 3- hydroxyl group to form the desired 11,8,l2-epoxy-21- ol-3,20dione acylate.

3. The method of making 11,12epoxypregnane 3,20-dione which comprises oxidizing using an oxidizing agent selected from the group consisting of chromic acid HOMN ffm CHOH References Cited in the file of this patent UNITED STATES PATENTS Reichsten July 9, 1946 Murray et a1 Aug. 18, 1953 Wettstein Feb. 19, 1957 Johnson et a1 12111.27, 1959 Herzet a1 Ian. 29, 1963 OTHER REFERENCES Herz et al.: J.A.C.S., vo178, pp. 2017-18, May 5, 1956. 

1. THE METHOD OF MAKING CHEMICAL COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF 11B,12B-EPOXYALLOPREGNANE3,20-DIONE AND 11B,12B-EPOXYALLOPREGNANE-3,20-DIONE WHICH COMPRISES OXIDIZING A COMPOUND HAVING THE FOLLOWING FORMULA: 